Ceramics have for many years been used for local applications, e.g. as bone void filler in clinical settings or in different forms of drug delivery systems for controlled and/or targeted delivery therapy. Many of the ceramics used are bioresorbable (or biodegradable) and various ceramics based on calcium salts, such as calcium phosphate or calcium sulphate systems, have been described. These ceramics are often referred to as hydratable or hydrating ceramics due to their ability to react chemically with water to solidify by forming hydrates. Some hydrating ceramics are considered stable in a biological environment, e.g. hydroxylapatite and calcium silicates
The bioresorbable ceramics have many favourable properties for use as implants or in controlled release applications in pharmaceutical formulations compared to e.g. polymers (such as polylactic acids and poly(lactic-co-glycolic-acids)) by their biocompatibility and bioresorbability. In general, the bioresorbable ceramics are non-toxic and are based on molecules which normally occur in the living tissues of mammals. Calcium sulphate is particularly attractive since it is a resorbable and biocompatible material, i.e. it disappears over time.
In general a composition is prepared by mixing hydratable ceramic, such as calcium sulphate, with water and e.g. a medicament or a bone matrix to provide a paste to be implanted as such or in a solid form. To minimize surgery, it is desirable to inject the paste into the body or organ through a small size cannula. However, mixing calcium sulphate and water results in a rapid onset of solidification, which reduces the time that the surgeon has to apply the paste before it solidifies, and also makes it difficult in praxis to eject the paste through a small sized cannula. In order to minimize the surgical intervention it is desirable to achieve a composition which has a prolonged solidification time, and an enhanced ejectability from a small sized cannula, whereby the composition can be implanted into the body without surgery, or with minimal surgery only.
The aim of the present invention is to make a composition that is injectable through a small cannula into the body of a subject, and which composition has a prolonged solidification time.
The inventors found this achievable by using a composition comprising an aqueous solution of carboxymethylcellulose, notably the sodium salt (Na-CMC), calcium sulphate hemihydrate (CaSO4.½H2O), and, optionally particles of calcium sulphate dihydrate (CaSO4.2H2O).
Na-CMC is commonly used as thickener, binder, stabilizer, and suspending agent in various forms of compositions. However, the inventors of the present invention have found it possible to control three important parameters of a composition by small adjustments of the Na-CMC concentration; namely the miscibility of the calcium sulphate hemihydrate powder with water; the ejectability of the formed paste through a thin needle, cannula, and/or biopsy cannula; and the retardation of the solidification time of the paste.
An important aspect of this composition is that Na-CMC is in an aqueous form before it is mixed with CaSO4.½H2O. As Na-CMC is slowly soluble in water, the aqueous form may be obtained by mixing Na-CMC with water, stirring this mixture for a few hours. The aqueous solution of completely dissolved Na-CMC is then mixed with CaSO4.½H2O just before use of the resulting paste. Optionally, the aqueous solution of Na-CMC can be sterilized by autoclaving and possibly also by sterile filtration, if the viscosity is not too high. Na-CMC is considered to be completely dissolved in a medium when a clear transparent thermodynamically stable solution is observed.
In addition, Na-CMC may also be provided in dry form, preferably as a thin film or a freeze-dried powder. In any event, if Na-CMC or another carboxymethylcellulose is used it is important to ensure that the carboxymethylcellulose relatively fast dissolves. Normally, Na-CMC has a relatively slow dissolution rate, which means that the properties of Na-CMC cannot be utilized within the 5-15 min available from establishment of the ready-to-use composition and to the injection and solidification of the composition. Accordingly, if carboxymethylcellulose is employed in dry form it should be either in form of micronized powder, lyophilized powder or as a thin film. Another possibility could be to incorporate a wetting agent in the composition, provided that such an agent does not have any negative impact on the ready-to-use composition.
By doing this, the inventors have achieved a composition that enables them to control the solidification time and also enables injection from a small needle in a syringe. Further, it has been found that this composition is retaining an acceptable miscibility. In addition, the composition does not require any addition of acid or acidic solution, such as aqueous acetic acid, to control the solidification time.
In US 2006/205652 is disclosed a composition in the form of a paste, gel or liquid for the delivery of synthetic heparin-binding growth factor analogues for bone or cartilage repair. In some aspects of the invention the composition can comprise a calcium sulphate compound and Na-CMC (gelling agent). However, the calcium sulphate compositions disclosed in the examples are not in hydratable form as calcium sulphate dihydrate is employed. Furthermore, in the examples disclosed a surfactant in (Pluronic) is being used in the solutions of Na-CMC.
EP1208850 discloses an osteogenesis promoter sustained-release paste that comprises an osteogenesis promoter, a calcium component and a viscosity-increasing agent. There are no examples showing a ready-to-use composition containing a hydratable calcium sulphate ceramic (e.g. calcium sulphate hemihydrate) and Na-CMC.
In WO 2007/104549 is disclosed a highly densified composition comprising e.g. calcium sulphate in the form of a calcium sulphate hemihydrate and a gelling or swelling agent which may include Na-CMC for the treatment of benign prostate hyperplasia. However, there are no examples showing a ready-to-use composition containing a hydratable calcium sulphate ceramic with Na-CMC only examples in which methylcellulose is used together with acetic acid.
In WO 2004/000334 is described a bone graft substitute composition which may comprise calcium sulphate, a mixing solution such as sterile water and a plasticizing material. However, no examples are given of a combination of Na-CMC and calcium sulphate.
JP56026756 discloses and discusses a method for producing alpha gypsum hemihydrate including carboxymethylcellulose under high pressure to result in a dry alpha gypsum hemihydrate. The solidification times disclosed are in the order of 1 hour or more and it is furthermore an object of JP56026756 to present gypsum structures having a light weight structure (porous bubble inclusion) with very high stability in the order of 6 months or more in water. However there is no disclosure of any method or composition according to present invention as is not an object of present invention to produce dry CaSO4.½H2O containing carboxymethylcellulose.
Thus, to the best of the inventors knowledge, no one have described a composition comprising Na-CMC, calcium sulphate hemihydrate and, optionally, sulphate dihydrate which, by specific adjustments of the Na-CMC concentration in the composition, gives a good miscibility of the calcium sulphate hemihydrate powder with an aqueous medium (e.g. water), an acceptable ejectability of the formed paste through a thin needle, and sufficient retardation of the solidification time of the paste to allow handling and administration of the ready-to-use composition without unnecessary prolongation of the solidification to avoid inappropriate spreading or clearance from the administration site.